Download Lecture 3

CLINICAL GENETICS
(MTD-356)
Lecture 3
Same Genetic Mutation,
Different Genetic Disease
Phenotype

Three individuals carry the same diseasecausing mutation; two suffer from the
disease but exhibit different symptoms,
while the third is completely unaffected.
Why?
For many inherited diseases, the same
mutation is not always expressed in all
individuals who carry it.
 moreover, when the mutation is expressed, it
is not always expressed in the same way.
 These findings are the basis for the concepts
of penetrance and expressivity.
 Penetrance measures the proportion of
a population of individuals who carry a
disease-causing allele and express the related
disease phenotype.
 Expressivity measures the extent to which
a genotype shows its phenotypic expression.

Example
Retinoblastoma is a cancer of the retina that primarily
affects children and is caused by mutations in
the Rb gene.
 Interestingly, not all people who carry this mutation
suffer from retinoblastoma.
 For instance, two sisters could inherit the same
mutation from their parents, and one might be affected
by thedisease, while the other is not.
 Perhaps even more interestingly, retinoblastoma is not
alone in this regard; there are numerous other inherited
diseases in which the same mutation is not expressed in
all the individuals who carry it. These findings illustrate a
concept that geneticists refer to as penetrance.






Penetrance is a measurement of the proportion of individuals
in a population who carry a disease-causing allele and express
the disease phenotype.
In the case of retinoblastoma, because not all individuals who
carry the mutation are affected by the disease, this condition
is said to display incomplete or reduced penetrance.
Other diseases with incomplete penetrance include
Huntington's disease and breast cancer.
In contrast to these examples, a disease shows complete
penetrance if all of the individuals who carry the related gene
are affected by the disease.
For instance, the inheritance of a specific point mutation in
the fibroblast growth factor receptor 3 gene (FGFR3) always
results in the disorder achondroplasia, which is characterized
by abnormal bone growth and dwarfism.
Factors Affecting Gene Expression







Penetrance is how often a gene is expressed.
It is defined as the percentage of people who have the gene and who
develop the corresponding phenotype.
A gene with incomplete or low penetrance may not be expressed
even when the trait is dominant or when it is recessive and the gene
responsible for that trait is present on both chromosomes.
Penetrance of the same gene may vary from person to person and
may depend on a person's age.
Even when an abnormal allele is not expressed (nonpenetrance), the
unaffected carrier of the abnormal allele can pass it to children, who
may have the clinical abnormality.
In such cases, the pedigree appears to skip a generation.
However, some cases of apparent nonpenetrance are due to the
examiner's unfamiliarity with or inability to recognize minor
manifestations of the disorder.
complete penetrance. The allele is said to have
complete penetrance if all individuals who have the
disease-causing mutation have clinical symptoms of the
disease.
 highly penetrant. If an allele is highly penetrant, then
the trait it produces will almost always be apparent in an
individual carrying the allele.
 incomplete penetrance or reduced penetrance.
Penetrance is said to be reduced or incomplete when
some individuals fail to express the trait, even though
they carry the allele.
 low penetrance. An allele with low penetrance will
only sometimes produce the symptom or trait with
which it has been associated at a detectable level. In
cases of low penetrance, it is difficult to distinguish
environmental from genetic factors.

Why Do Phenotypes Show Differences in Penetrance?



Penetrance can be difficult to determine reliably, even for genetic diseases that
are caused by a single polymorphic allele. For many hereditary diseases, the onset
of symptoms is age related, and is affected by environmental codeterminants such
as nutrition and smoking, as well as genetic cofactors and epigenetic regulation of
expression:
Age-related cumulative frequency. Penetrance is often expressed as a
frequency, determined cumulatively, at different ages. For example, multiple
endocrine neoplasia 1 (MEN 1), a hereditary disorder characterized
by parathyroid hyperplasia and pancreaticislet-cell and pituitary adenomas, is
caused by a mutation in the menin gene on human chromosome 11q13. In one
study the age-related penetrance of MEN1 was 7% by age 10 but increased to
nearly 100% by age 60.
Environmental modifiers. Penetrance may be expressed as a frequency at a
given age, or determined cumulatively at different ages, depending on
environmental modifiers. For example, several studies
of BRCA1 and BRCA2 mutations, associated with an elevated risk
of breast and ovarian cancer in women, have examined associations with
environmental and behavioral modifiers such as pregnancies, history of breast
feeding, smoking, diet, and so forth.
Genetic modifiers. Penetrance at a
given allele may be polygenic, modified by
the presence or absence of polymorphic
alleles at other gene loci. Genome
association studies may assess the
influence of such variants on the
penetrance of an allele.
 Epigenetic regulation. Example ...
genomic imprinting by the paternal or
maternal allele.

Expressivity is the extent to which a gene is
expressed in one person.
 It can be graded as a percentage; e.g, when a
gene has 50% expressivity, only half the
features are present or the severity is only half
of what can occur with full expression.
 Expressivity may be influenced by the
environment and by other genes, so people
with the same gene may vary in phenotype.
 It can vary even among members of the same
family.

Neurofibromatosis





Neurofibromatosis is a disease caused by mutations
in the neurofibromin gene.
These mutations can cause the Schwann cells in an
affected individual's nervous system to grow into
tumors called neurofibromas, which appear as caféau-lait colored spots or bumps under the skin.
These tumors can result in skeletal abnormalities and
neurological problems.
However, not all people who have the mutated
neurofibromin gene are equally affected by this
condition.
Research has shown that family members who carry
the same mutated gene can exhibit a range of
symptoms, with some individuals experiencing much
more severe symptoms than others, although they all
carry the same allele.
Holoprosencephaly





Holoprosencephaly is a condition in which the embryonic
forebrain does not correctly divide into two lobes.
To date, scientists have described nine types of
holoprosencephaly caused by deletions or duplications in
various genes and chromosomal regions.
In 1993, researcher Amanda Collins and her colleagues
studied a single large family with multiple children affected
with holoprosencephaly, and they noted variable expressivity
of the disease in the affected family members.
In the most severe cases, holoprosencephaly resulted in
death. In contrast, in the mild cases, the family members had
near-normal to normal brain development and only minor
facial deformities, such as a single upper central incisor.
Other studies have shown that this disease also displays
incomplete penetrance.
Van der Woude Syndrome
Van der Woude syndrome is a dominantly inherited
developmental disorder that causes cleft lip and/or cleft
palate.
 This condition results from mutations in a single gene that
encodes for a protein called interferon regulatory factor 6.
 Studying a large family of seven generations affected with
Van der Woude syndrome, Janku et al. noted that the
disorder displayed both incomplete penetrance and variable
expressivity. Sometimes, individuals who did not realize they
were affected were diagnosed with mild versions of the
disorder upon careful examination. Most patients had
characteristic lip pits, which were often observed alone and
sometimes with other symptoms. Meanwhile, lip and palate
clefts were observed in around one-fifth of individuals
(Janku et al., 1980).
